1. Field of Invention
The present invention relates to [3-(C5-14 alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-phenyl and [3-(C5-14 alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-heteroaryl derivatives having anti-tumor activity. The present invention also relates to pharmaceutical compositions used for treating tumor bearing mammals in need of such treatment with the compounds of the invention, and particularly for treating mammals, including humans, suffering from breast and/or prostate cancer with the compounds of the invention.
2. Brief Description of Background Art
U.S. Pat. Nos. 6,495,552; 6,291,677; 6,344,463; 6,048,873; 6,124,455; 6,147,224; 5,672,710; 5,677,323; 5,739,338; 5,556,996; 5,602,130; 5,616,712; 5,278,318; 5,399,561; 5,498,755; 4,810,804; 5,739,338, 5,780,647, 6,127,382 and 6,469,028 disclose compounds which include a tetrahydroquinoline or dihydroquinoline nucleus. The compounds of these patents are generally considered to act as retinoids which are generally known and accepted in the art to be useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. Generally speaking, among the conditions treatable with retinoids or like compounds are premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and Kaposi""s sarcoma. Nevertheless, depending on the receptor sites through which they act and on other known and unknown factors, retinoid or like compounds can have different modes of action, particularly as anti-tumor activity is concerned.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356.
The present invention is directed to certain Nxe2x80x94C5-11 alkyl and like xe2x80x9clong chainxe2x80x9d substituted tetrahydroquinolin-2-one derivatives, which surprisingly have significantly better anti-tumor activity than their analogs where the N is substituted with a shorter chain alkyl (or like) groups.
The present invention relates to compounds of Formula 1
where X is O or S;
m is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 3;
R1 is independently H, or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br or I;
R3 is alkyl of 5 to 11 carbons, alkenyl of 5 to 11 carbons and having one or two double bonds, alkynyl of 5 to 11 carbons and having one to two triple bonds, alkenyl-alkynyl having 5 to 11 carbons and one double and one triple bond, or
R3 is (CH2)r-phenyl-(CH2)sxe2x80x94(CH3)t where r is an integer having the values of 0 to 7, s is an integer having the values of 0 to 6, and t is an integer having the values of 0 to 1, with the provisos that the sum of r, s and t is in the range of 1 to 7, the phenyl group is 1,3 (meta) or 1,4 (para) substituted with the (CH2)r and (CH2)sxe2x80x94(CH3)t groups, the phenyl group optionally being further substituted with one or two R4 groups;
R4 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br or I, alkoxy of 1 to 3 carbons, thioalkoxy of 1 to 3 carbons; NO2, amino, alkylamino or dialkylamino where the alkyl group has 1 to 3 carbons;
Y is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R4 groups;
A is (CH2)q where q is 0-5, branched chain alkyl having 3-6 carbons, cycloalkyl having 3-6 carbons, alkenyl having 2-6 carbons and 1 or 2 double bonds, alkynyl having 2-6 carbons and 1 or 2 triple bonds, and
B is COOH, COOR8, CONR9R10, xe2x80x94CH2OH, CH2OR11, CH2OCOR11, CHO, CH(OR12)2, CHOR13O, xe2x80x94COR7, CR7(OR12)2, CR7OR13O, or tri-C1-6 alkylsilyl, where R7 is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R8 is an alkyl group of 1 to 10 carbons, OCH2OC-1-3 alkyl or OCH2OCOC-1-3 alkyl, or trimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R8 is phenyl or C1-6 alkylphenyl, R9 and R10 independently are hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or C1-6 alkylphenyl, R11 is C1-6 alkyl, phenyl or C1-6 alkylphenyl, R12 is C1-6 alkyl, and R13 is divalent alkyl radical of 2-5 carbons, or a pharmaceutically acceptable salt of said compound.
The present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of tumor bearing mammals with pharmaceutical compositions containing one or more compounds of Formula 1, and particularly to methods of treating breast cancer and prostrate cancer with compounds of the invention.
The term alkyl refers to and covers any and all groups which are known as normal alkyl and branched-chain alkyl.
A pharmaceutically acceptable salt may be prepared for any compound in this invention having a functionality capable of forming a salt, for example an acid functionality. A pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or untoward effect on the subject to which it is administered and in the context in which it is administered.
Pharmaceutically acceptable salts may be derived from organic or inorganic bases. The salt may be a mono or polyvalent ion. Of particular interest are the inorganic ions, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules.
The compounds of the present invention include at least one olephinic double bonds about which trans and cis (E and Z) stereoisomerism can exist. Unless specifically indicated by formula or chemical name the compounds of the present invention, including the preferred embodiments can have both the trans and cis (E and Z) orientations of substituents relative to the double bond or bonds. Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms. The scope of the present invention is intended to cover the trans and cis (E and Z) isomers as specifically shown and/or named, as well as pure enantiomers (optical isomers), diastereomers, mixtures of diastereomers and racemic mixtures of enantiomers.
Reaction Scheme 1 discloses a presently preferred synthetic route to compounds of the invention. In accordance with Reaction Scheme 1 a 4-bromo-aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 3 in an aprotic neutral solvent in the presence of an acid acceptor, such as triethyl amine (TEA), to provide the phenyl amide derivative of Formula 4. The aniline derivative of Formula 2 is already substituted with the R4 groups, (the variables R4 and n are defined as in connection with Formula 1) although the 4-bromo aniline used for the preparation of the presently preferred compounds of the invention is unsubstituted (n=0). The substitituted anilines of Formula 2 are either available commercially, or can be prepared in accordance with the chemical scientific and patent literature, or by such modifications of known synthetic procedures that are readily apparent to those skilled in the art. 
In the formula (Formula 3) of the acryloyl chloride derivative the variables R1, R2 and m are defined as in connection with Formula 1. An example of the acryloyl chloride derivative of Formula 3 that is used for the synthesis of the presently preferred compounds of the invention is commercially available 3,3-dimethylacryloyl chloride (R1 is methyl and m=0). Acrylic acid derivatives of Formula 3 can also be obtained, generally speaking, in accordance with the chemical scientific and patent literature, or by such modifications of known synthetic procedures that are readily apparent to those skilled in the art. The acrylic acid amide derivative of Formula 4 is cyclized under Friedel Crafts conditions to provide the 3,4-dihydro-1H-quinolin-2-one derivative of Formula 5.
The 3,4-dihydro-1H-quinolin-2-one derivative of Formula 5 is reacted with tributyl(1-ethoxyvinyl)tin to introduce an acetyl group into the 6 position of the quinoline nucleus and to provide a 6-acetyl-3,4-dihydro-1H-quinolin-2-one derivative of Formula 6. The R3 group (R3 is as defined in connection with Formula 1) is introduced into the molecule by treatment of the compound of Formula 6 with a reagent of the formula R3xe2x80x94I and a strong base, such as sodium hydride in a polar aprotic solvent, such as dimnethylformamide (DMF). Instead of the iodo derivative R3xe2x80x94I, other alkylating agents of the formula R3xe2x80x94X1 (where X1 is a leaving group) could also be used in this reaction to provide a 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7. The 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7 is reacted with a bromophenyl or bromo heteroaryl aldehyde of Formula 8 to give the 1-alkyl-6-[3-(bromo phenyl or bromo-heteroaryl)-acryloyl]-3,4-dihydro-1H-quinolin-2-one of Formula 9. The bromo compound of Formula 9 is reacted with carbon monoxide in the presence of 1,3-bis(diphenylphosphino)propane (DPPP), palladium acetate (Pd(OAc)2), triethylamine (TEA) in dimethylformamide and ethanol and thereafter with base (such as NaOH or KOH) to provide [3-(1-alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-benzoic or heteroaryl carboxylic acids of Formula 10.
Alternatively, the 6-acetyl-1-alkyl (or 1-phenylalkyl) 3,4-dihydro-1H-quinolin-2-one derivative of Formula 7 is reacted with an aldehyde of Formula 11 to provide [3-(1-alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-benzoic or heteroaryl compounds of Formula 12.
In the formulas of the reagents of Formula 8 and Formula 11 the variables Y(R4) and Axe2x80x94B are defined as in connection with Formula 1. The reagents of Formula 8 are bromo substituted benzaldehydes, bromo substituted naphthyl-aldehydes or bromo substituted heteroaryl aldehydes which, generally speaking, can be obtained in accordance with the chemical scientific and patent literature, or by such modifications of known synthetic procedures that are readily apparent to those skilled in the art. An example for the reagent of Formula 8 that is used for the synthesis of one or more preferred compounds of the invention is 4-bromobenzaldehyde. Other examples are 3-bromobenzaldehyde, 5-bromo-pyridine-2-aldehyde, 4-bromo-pyridine-2-aldehyde, 4-bromo-thiophene-2-aldehyde, 5-bromo-thiophene-2-aldehyde, 4-bromo-furan-2-aldehyde, and 5-bromo-furan-2-aldehyde.
In the preparation of several preferred exemplary compounds of the invention the reagent of Formula 11 is 4-carboxybenzaldehyde. Examples of other reagents within the scope of Formula 11 are: 5-carboxy-pyridine-2-aldehyde, 4-carboxy-pyridine-2-aldehyde, 4-carboxy-thiophene-2-aldehyde, 5-carboxy-thiophene-2-aldehyde, 4-carboxy-furan-2-aldehyde and 5-carboxy-furan-2-aldehyde. These compounds are available in accordance with the chemical literature; see for example Decroix et al., J. Chem. Res.(S), 4: 134 (1978); Dawson et al., J. Med. Chem. 29:1282 (1983); and Queguiner et al., Bull Soc. Chimique de France No. 10, pp. 3678-3683 (1969). The condensation reaction between the compounds of Formula 7 and Formula 8 or between the compounds of Formula 7 and Formula 11 is conducted in the presence of base in an alcoholic solvent. Preferably, the reaction is conducted in methanol in the presence of sodium hydroxide. Those skilled in the art will recognize this condensation reaction as an aldol condensation, and in case of the herein described preferred examples (condensing a ketone of Formula 7 with an aldehyde of Formula 8 or of Formula 11) as a Claisen-Schmidt reaction. (See March: Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, pp. 694-695 McGraw Hill (1968).
The [3-(1-alkyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-3-oxo-propenyl]-benzoic or heteroaryl compounds of Formula 12 can be converted to the corresponding 2-thio analogs of Formula 13 by treatment with [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphatane-2,4-disulfide. (Lawesson""s reagent). The compounds of Formulas 10, 12 and 13 are within the scope of Formula 1 and within the scope of the present invention. Those of skilled in the art will readily recognize that several synthetic transformations can be performed on the compounds of Formulas 10, 12 and 13 to obtain other compounds which are still in the scope of the invention, keeping the scope of the Axe2x80x94B group in mind. Esterification and/or saponification, homologation, formation of carboxylic acid amides, and reduction of carboxylic acid or ester group to the aldehyde or the primary alcohol level serving as examples. These reactions per se are well known in the art and can be readily performed by those skilled in the art to obtain xe2x80x9chomologs and derivativesxe2x80x9d which are still within the scope of the invention and wherein the Axe2x80x94B group has the scope defined in connection with Formula 1.
Referring now to Formula 1, in the preferred compounds of the invention the variable R1 represents alkyl groups of 1 to 3 carbons, and even more preferably methyl. Still more preferably the 1,2,3,4-tetrahydroquinoline group is substituted in the 4 position by geminal dimethyl groups, and still further substitution of the non-aromatic portion by additional R2 groups is presently not preferred. The R3 group of the preferred compounds is alkyl of 5 to 11 carbons, or phenylalkyl, even more preferably alkyl of 6 to 9 carbons, or phenylethyl. The X group of the presently preferred compounds is oxygen. Preferred R4 groups are alkyl of 1 to 3 carbons, F, Cl, Br, I, or alkoxy of 1 to 3 carbons. Even more preferably the aromatic portion of the tetrahydroquinoline nucleus is substituted only in the 6 position by the 3-oxo-propenyl-phenyl or by the 3-oxo-propenyl-heteroaryl group (the variable n in Formula 1 is zero).
In the presently preferred compounds of the invention the Y group is phenyl and there is no optional R4 substituent. Compounds are also preferred where the Y group is pyridyl, thienyl or furyl. Preferred Axe2x80x94B groups are (CH2)qxe2x80x94COOH, (CH2)qxe2x80x94COOR8, and (CH2)qxe2x80x94CONR9R10 and preferably q is zero. Even more preferably the Axe2x80x94B group is COOH or COOR8 where R8 is preferably alkyl of 1 to 3 carbons, OCH2OC-1-3 alkyl or OCH2OCOC-1-3 alkyl. The phenyl group is preferably 1,4 (para) substituted by the 3-oxo-propenyl and Axe2x80x94B groups. When the Y group is pyridyl, it is preferably 1,5-substituted by the 3-oxo-propenyl and Axe2x80x94B groups.